The depolarizing action of 5-hydroxytryptamine on rabbit vagal afferent and sympathetic neurones in vitro and its selective blockade by ICS 205-930.

Abstract

Depolarizing responses to 5-hydroxytryptamine (5-HT) were recorded from rabbit nodose (NG) and superior cervical (SCG) ganglia using the sucrose-gap technique. The antagonist potency and selectivity of ICS 205-930 ([3 alpha-tropanyl]-1H-indole-3-carboxylic acid ester) were investigated. In NG, 5-HT (5 to 80 nmol) evoked depolarizations of graded amplitude. The ED50 was 18.2 (10.9-30.5) nmol (geometric mean, 95% confidence limits). Responses were blocked surmountably by ICS 205-930, 10(-11) and 10(-10) M, the threshold for blockade being below 10(-11) M. Parallel, rightward shifts in dose-response curves were seen with these concentrations of antagonist, but at higher concentrations (10(-9) and 10(-8) M) there was a further rightward shift with reduction in slope and maximum of the curves. In SCG, where 5-HT (20 to 320 nmol) evoked depolarizations of graded amplitude and the ED50 was 55.8 (22.3-139.6) nmol (geometric mean, 95% confidence limits), ICS 205-930 had a similar inhibitory effect to that observed in NG. The apparent pA2 values for the surmountable blockade produced by ICS 205-930 at concentrations of 10(-11) and 10(-10) M were 10.2 +/- 0.2 for NG and 10.4 +/- 0.1 for SCG (means +/- s.e. mean). ICS 205-930 was selective in its action since it had no effect on dimethylphenylpiperazinium (DMPP) responses in either ganglion or on GABA responses in NG. This study provides quantitative evidence on the blocking action of ICS 205-930 at neuronal 5-HT receptors using a technique that allows the depolarizing responses evoked by the amine to be directly recorded.